The Mentored Patient-Oriented Research Career Development Award (K23) will enable Dr. Edward D. Siew to develop into an independent investigator in the clinical and translational study of acute kidney injury (AKI) and establish an independent research program focused on critical illness-associated kidney injury. Through the availability of a carefully constructed program of didactic activities in clinical proteomics, advanced epidemiology, and biostatistics;intensive mentorship by local and international experts;and direct experience in the design, implementation, and interpretation of data derived from a large prospective cohort of critically ill adults, Dr. Siew will use this award to become a highly trained investigator in AKI research. The primary scientific aims of this proposal are to examine the independent and additive impact of biological markers of injury for the early detection and prognosis of AKI in the critically ill and to apply emerging proteomic technology towards the discovery of novel protein markers able to predict progression of injury at the time of early diagnosis. Despite advances in the provision of care, AKI remains a common and devastating occurrence in the critically ill and an independent predictor of morbidity and mortality. Attempts at translating promising interventions into improved outcomes in AKI have been limited belated and unreliable markers of injury (i.e. changes in serum creatinine and urine output) that provide little information on the timing and mechanisms of ongoing injury. These limitations are further magnified in a mixed ICU patient population where the timing and extent of injury is more difficult to define. Using a large, well- phenotyped prospective cohort of critically ill adults (The Validation of Biomarkers for Acute Lung Injury Diagnosis/VALID Study), this proposal will test the hypothesis that a biomarker panel consisting of specific indicators of kidney injury will have independent and additive value for the early diagnosis and prognosis of AKI in a mixed adult ICU population (Specific Aims 1a and 1b). The candidate will learn to apply emerging proteomic techniques such as liquid- chromatography tandem mass-spectrometry (LC-MS-MS) towards discovering and verifying new potential protein targets able to predict progression of injury at the time of initial AKI diagnosis (Specific Aim 2). The proposed research plan will further define the role of promising candidate markers in providing additional pathophysiologic insight, enhancing risk stratification, and facilitating clinical trial enrollment. Further, the research included in this proposal will also provide this candidate with the skill set and experience to develop into a successful independent investigator able to make significant contributions toward improving the care of patients with this disease. PUBLIC HEALTH RELEVANCE: Progress towards improving outcomes in acute kidney injury (AKI) in the critically ill has been limited by the use of belated and unreliable markers of injury (i.e. serum creatinine, urine output). The proposed career development award application seeks to leverage the strengths of a large well-characterized cohort of 2550 critically ill adult patients (VALID - HL081332). The overarching aims are to validate candidate biological markers of injury able to improve the accuracy and timeliness of AKI diagnosis and prognosis as well as to apply emerging proteomic technology towards identifying patients at risk for progressive injury.